GLUT4 is the predominant facilitative glucose transporter expressed in such insulin-responsive tissues as adipose tissue and cardiac and skeletal muscle (2, 19). Under basal conditions, GLUT4 is sequestered from the plasma membrane in a unique intracellular compartment. In response to various stimuli (e.g., insulin, contraction, hypoxia), GLUT4 translocates to the cell surface and is mostly responsible for the increase in glucose uptake (20–24).
In a previous study, the insulin-sensitive glucose transporter, GLUT4, was genetically ablated in mice (1). Unexpectedly, GLUT4-null mice were able to maintain normal glycemia with moderate fed hyperinsulinemia, even though in vitro studies showed the null muscle to be highly insulin resistant (1, 3). Interestingly, oxidative soleus muscle of female GLUT4-null mice retained a significant insulin-stimulated glucose uptake (3). Furthermore, skeletal muscle of GLUT4-null mice maintained normal levels of high energy phosphate pools (25). However, unlike serum glucose level, fed serum free fatty acids and fasted ketone body levels were significantly decreased in GLUT4-null mice (1). The compensatory glucose uptake response was more robust in vivo under hyperglycemic clamp conditions, thereby suggesting that a glucose-sensitive glucose transport system or glucose sensor/receptor-like molecule was activated in highly oxidative tissues in the absence of GLUT4.
Cloning efforts have led to the isolation of a novel cDNA encoding GLUTx (4–7), a protein which is also referred to as GLUTx1 and GLUT8. GLUTx has significant homology to facilitative glucose transporters such as GLUT4 and GLUT1, and has conserved amino acids known to be important in glucose binding. Additionally, GLUTx contains amino acid motifs present only in the glucose sensor/receptors SNF3 and RGT2. Using in situ hybridization techniques, GLUTx has been detected in the cerebellum and hippocampus of GLUT4-null and wild-type mice, and in other areas corresponding to the “obesity center” of the human brain (e.g., the hypothalamus). These findings suggest that GLUTx functions as a glucose sensor/receptor that assists in maintenance of normal blood glucose.